Fungi are eukaryotic microorganisms. Fungi can occur as yeasts, molds, including mildews, or as a combination of both forms. Yeasts are microscopic fungi consisting of solitary cells that reproduce by budding. Molds, in contrast, occur in long filaments known as hyphae, which grow by apical extension. Hyphae can be sparsely septate to regularly septate and possess a variable number of nuclei. Regardless of their shape or size, fungi are all heterotrophic and digest their food externally by releasing hydrolytic enzymes into their immediate surroundings (absorptive nutrition). The words “mold” and “fungus” and “yeast” and their various grammatical forms are generally used interchangeably herein except where a particular taxon is discussed.
Molds reproduce by releasing seed-like spores into their environment. Mold spores are seemingly ubiquitous. Given a suitable environment of appropriate temperature, humidity and nutrients, spores germinate and can infect one's living space leading to decay and discoloration of affected surfaces, as well as offensive odors and allergic reactions of inhabitants. [McGinnis et al., “Introduction to Mycology”, In: Baron S, editor, Medical Microbiology, 4th ed., Galveston, Tex., University of Texas Medical Branch at Galveston (1996).]
Many fungi can grow on wood products, ceiling tiles, cardboard, wallpaper, carpets, drywall (plasterboard or wallboard), fabric, plants, foods, insulation, decaying leaves and other organic materials, causing rot or decay of the cellulosic material. Such wood product-growing fungi are referred to herein as cellulose-supportable fungi. They possess specific enzymes that can digest cellulose and related polysaccharides. These fungi can typically also utilize another source of sugars for growth, but share an ability to grow on cellulose as a food source.
There is no universal antifungal/antimicrobial that is effective at inhibiting the growth of all fungal species. Even the inhibitory efficacy of known broad spectrum antifungals depends on the species of the organism (fungi in the case of antifungal), the environmental condition (e.g., temperature and humidity), and the substrate (e.g., food source). For example, as shown herein, antifungals can display very different inhibitory efficacy for cellulose-supportable fungi when the food source (paper/cellulosic substrate vs. potato dextrose broth) or the antifungal delivery system (inside dried latex paint matrix vs. in liquid culture medium) are different.
Fungal growths, or colonies, can start to grow on a damp surface within 24 to 48 hours. Fungi digest organic material, eventually destroying the material they grow on, and then spread to destroy adjacent organic material. In addition to the damage fungi can cause in a home, they can also cause mild to severe health problems.
Of the thousands of fungi that exist, some are or produce known allergens (aggravating or causing skin, eye, and respiratory problems), and a few fungi produce harmful mycotoxins that can cause serious problems. But all fungi, in the right conditions and at high enough concentrations, are capable of adversely affecting human health.
The potential for health problems occurs when people inhale large quantities of the airborne mold spores. For some people, however, a relatively small number of mold spores can cause health problems. Fungal infection can also occur on the skin of a person's body. Infants, children, immune-compromised patients, pregnant women, individuals with existing respiratory conditions, and the elderly are at higher risks for adverse health effects from mold.
Some of the common molds (fungi) present in indoor environments that can have an impact on human health are: Stachybotrys chartarum, Alternaria alternata, Penicillium chrysogenum, Aspergillus niger, Chaetomium globosum and Auerobasidium pullulans. 
The more serious health problems have been associated with the cellulose-supportable toxic black mold, Stachybotrys atra also called Stachybotrys chartarum. The mold is greenish-black and slimy, resembling tar or black paint. Spores of Stachybotrys chartarum are allergenic just like the spores from other mold species. Stachybotrys chartarum is classified as a toxic mold because it produces toxic chemicals called mycotoxins.
Stachybotrys typically feeds and grows only on repeatedly wetted materials that contain cellulose—from paper to ceiling tiles, drywall and any kind of wood. In most cases, this mold can be removed by a thorough cleaning with a 10% bleach solution. Severe mold infestations may require the assistance of a professional with experience in dealing with Stachybotrys. Dealing With Mold & Mildew In Your Flood Damaged Home, U.S. Department of Homeland Security, FEMA, fema.gov/pdf/rebuild/recover/fema_mold_brochure_english.pdf.
Alternaria alternata is another commonly encountered cellulose-supportable allergenic fungus. Brown segmented mycelia give rise to simple or solitary conidiophores, which may produce solitary apical spores, or a string of spores. Alternaria is one of the main allergens affecting children. In temperate climates, airborne Alternaria spores are detectable from May to November, with peaks in late summer and autumn.
Although A. alternata can be found on foodstuffs and textiles, with favorite habitats being soils, corn silage, rotten wood, compost, bird nests, and various forest plants. It is frequently found on water condensed on window frames. It is one of the most common mold spores found in dwelling dust in both North America and Europe.
The number of allergens in A. alternata extracts can range from 10 to 30, and few allergens are present in nearly all extracts studied [De Vouge et al., Int Arch Allergy Immunol 116(4):261-268 (1998)]. The presence of specific allergens, including the major allergens, depends very much on the growth conditions, and may vary during the growth cycle, being higher one day than another [Breitenbach et al., Chem Immunol 81:48-72 (2002); Portnoy et al., J Allergy Clin Immunol 91:773-782 (1993)]. Furthermore, the major allergens are secreted proteins, whereas the other allergens are intracellular proteins, and these are presented to the immune system in the spores of this mold, which are too large to reach the alveoli of the lung [Breitenbach et al., Chem Immunol 81:48-72 (2002)].
Penicillium is a common fungal contaminant in indoor environments. The spores of this mold are produced in dry chains and can easily be dispersed in the air. One of the most common species is Penicillium chrysogenum that produces several toxins of moderate toxicity, are allergenic and can infect immunocompromised individuals. Penicillium chrysogenum has been shown to induce a more robust allergic and inflammatory response at lower doses than house dust mite [Ward et al., Indoor Air 20:380-391 (2010)]. Thus, Penicillium chrysogenum and other common household molds, may play an important role in asthma development.
Aspergillus is another ubiquitous fungal contaminant whose spores can often be isolated from indoor air, but does not normally cause illness on healthy individuals. Allergens produced by Aspergillus niger and Aspergillus fumigatus can produce allergic reactions in humans. Aspergillosis is a group of diseases that can result from aspergillus infection. Individuals who suffer from asthma and other respiratory diseases are at a greater risk for these infections.
Aureobasidium is another common mold found in soil, wood, textiles, and indoor air environments. This yeast-like fungus is commonly found on caulking or damp window frames. Chronic exposure to Aureobasidium pullulans can lead to hypersensitivity pneumonitis. [Microorganisms in Home and Indoor Work Environments: Diversity, Health Impacts, Investigation and Control, Second Ed., Flannigan et al. Eds., Taylor and Francis Group, New York, 2011].
Other common indoor/environmental fungal contaminants include various species of Penicillium, Nucor, Ulocladium, Trichoderma, Acremonium, Chaetomium, Aspergillus, Cladosporium, Epicoccum, Rhizopus, and Aureobasidium [Horner et al., Appl. Environ. Microbiol. 70:6394-6400 (2004); Andersen et al., Appl. Environ. Microbiol. 77:4180-4188 (2011)], which are commonly isolated from indoor air and water damaged building materials. Many of the above fungi are known to produce cellulases and cause the degradation of paper and other cellulosic materials [Jerusik, Fungal Biol. Rev. 24:68-72 (2010)].
Latex paint is a general term that covers paints that use synthetic polymers such as acrylic, vinyl acrylic (PVA), styrene-acrylic, and the like as film-forming binders that are dispersed along with a colorant in an aqueous medium as the vehicle. The word “latex” is used because these paints form milky white emulsions in water when free of other pigments, just as does the true latex formed from a Hevea rubber plant.
A clear coating like a varnish primarily contains the binder and the vehicle. If a colorant such as a pigment is added to provide color and opacity to a varnish, one makes a paint.
Many commercially available latex paints contain fungus growth-inhibiting ingredients. Aside from usually-observed differences in activity against microbes such as fungi that are exhibited in aqueous media, incorporation of a fungus growth-inhibiting ingredient (fungicide) can provide a greater challenge to fungus growth inhibition relative to that exhibited in a Petri dish because of the encapsulation of the fungicide within the matrix of a dried paint film.
In the conventional model of an external paint film, there is a reservoir of fungicidal/antifungal active agent in the paint film, and there is also some biocide on the surface of the paint. As rain falls on the surface of the paint film, it washes away the biocide on the surface; however the biocide at the surface of the film is replenished by new biocide that is drawn from the reservoir. [Brown, “The Development of High-Performance Paint Film Biocides for Architectural Coatings”, Paint & Coatings Industry, BNP Media (Jul. 1, 2014).]
When there is a balance between the biocide rate of depletion from the surface and the biocide rate of migration from within the film, the coating will have long-term protection from microbial attack. When there is not a balance, the coating will fail more quickly.
Where the selected biocide has too high a water solubility, the coating will be well protected during an initial period of perhaps 12 to 18 months, but the biocide reservoir in the film will be quickly depleted and the coating will fail after that short initial period. Where the selected biocide has too low a water-solubility and a coated surface is first placed in the outdoor environment, there is an initial period where the coating will have high susceptibility to fungal attack because some of the non-fungicidal small-molecule paint ingredients leach from the coating film and serve as a nutrient source for the fungi. After the nutrients are washed away and the coating becomes less susceptible to fungal attack, if the fungicide selected has too low a water solubility, fungi can start to become established during the initial period of high susceptibility. In this case, there is biocide present at the surface of the film, but not enough biocide migrates from the biocide reservoir in the film to prevent the fungi from becoming established.
One common strategy for achieving long-term protection of the coating film is to combine a very low water solubility fungicide with a relatively high water solubility fungicide. The more water-soluble fungicide will migrate quickly through the film and will prevent the fungi from becoming established during the initial period of the coating's high microbial susceptibility. Over longer term of outdoor exposure, the less water-soluble biocide will continue to slowly migrate from the biocide reservoir in the coating film to the coating surface. Because the coating has lower microbial susceptibility after the initial time period, the level of the less-soluble biocide delivered to the coating's surface is sufficient to prevent microbial defacement. With this strategy, long-term protection of the coating can be achieved. [Brown, “The Development of High-Performance Paint Film Biocides for Architectural Coatings”, Paint & Coatings Industry, BNP Media (Jul. 1, 2014).]
The Brown article lists ten typical fungicides and algaecides used in the paint industry for dry film preservation. The article grouped the antifungal compounds by relative solubility in water to include: zinc pyrithione (ZnPT) [or zinc omadine (ZnOM)], chlorothalonil (CTL), carbendazim (BCM), and Irgarol® as low water solubility compounds (6-8 mg/L); diuron, dichlorooctylisothiazolinone (DCOIT), and terbutryn as having medium solubility in water [14-35 mg/L]; and octylisothiazolinone (OIT), n-butyl-benzisothiazolinone (BBIT), and iodopropynylbutyl-carbamate (IPBC) as having high water solubility [168-700 mg/L].
Illustrative solubilities of six commercially available fungicidal agents used in surface coating applications, including some of those noted by Brown, are listed in Table 1 hereinafter. Brown characterized IPBC and OIT as being among those fungicides exhibiting “high water solubility” that would be formulated with another less water soluble fungicide. Following Brown's guideline, one would classify chlorothalonil and thiabendazole as having “low water solubility” whereas triclosan would have extremely “high water solubility”.
Benzoxaborole preparations and uses are the subject of several U.S. Patents, including U.S. Pat. Nos. 7,582,621; 7,767,657; 7,816,344; and 8,168,614. Many of those compounds are used as antibiotics, with U.S. Pat. No. 7,816,344 teaching at column 1, lines 37-41, certain classes of oxaboroles of Formula A, below, that are monosubstituted at the −3, 6- or −7 position or disubstituted at the 3-/6-, or −3/-7 positions
are effective anti-bacterial agents.
U.S. Pat. No. 7,767,657 teaches and claims that a 5-fluorobenzoxyborole of Formula B and
its salts are useful in a composition for topical or foliar administration to an animal suffering from an infection from a microorganism, and particularly exemplifies yeasts and fungi as the microorganism treated. 5-Fluorobenzoxyborole is an antifungal agent in that it suppresses the ability of fungal growth, inter alia, by inhibiting leucyl-transfer RNA synthetase, an enzyme that plays a pivotal role in fungal protein synthesis.
An ethanolic solution containing 5% (w/w) 5-fluorobenzoxy-borole is commercially available for treating onychomycosis of the toenail due to Trichophyton rubrum or Trichophyton mentagrophytes from Anacor Pharmaceuticals, Inc., under the name Kerydin®. The United States Adopted Names (USAN) name for 5-fluorobenzoxyborole is tavaborole.
U.S. Patent Publication No. 20140259230 published Sep. 11, 2014 teaches the use of several oxaborole compounds for protecting plants and plant propagation materials from phytopathogens. One group of oxaboroles were disclosed to be those of Formula B-1 in which the possible combinations of R,
R7 and X amount to more than 100 million compounds.
Those substituents in a further preferred embodiment were F for R7, CH2 for X and H was R, C1-C4alkyl optionally substituted by —NR3R4 wherein R3 and R4 are each independently hydrogen, optionally substituted C1-C4alkyl. A composition containing a compound of Formula B-1 was said to be useful in a method of protecting plants or plant propagation materials against phytopathogenic fungi belonging to several classes. The above published application teaches the use of several oxaboroles at concentrations ranging from 200 to 20 parts per million (ppm) to obtain between 80 and 20 percent control of fungal growth on infected plants, seeds and plant propagation materials.
As disclosed hereinafter, it has been found that a benzoxaborole of Formula C can be successfully added to a latex paint composition to provide protection from fungal growth on a non-living cellulosic substrate.